81 research outputs found
Ser364 of connexin43 and the upregulation of gap junction assembly by cAMP
The assembly of gap junctions (GJs) is a process coordinated by growth factors, kinases, and other signaling molecules. GJ assembly can be enhanced via the elevation of cAMP and subsequent stimulation of connexon trafficking to the plasma membrane. To study the positive regulation of GJ assembly, fibroblasts derived from connexin (Cx)43 knockout (KO) and wild-type (WT) mice were transfected with WT Cx43 (WTCx43) or mutant Cx43. GJ assembly between untransfected WT fibroblasts or stably transfected WTCx43/KO fibroblasts was increased two- to fivefold by 8Br-cAMP, and this increase could be blocked by inhibition of cAMP-dependent protein kinase (PKA) or truncation of the Cx43 COOH terminus (CT). Although serine 364 (S364) of the Cx43 CT was determined to be a major site of phosphorylation, the molar ratio of Cx43 phosphorylation was not increased by 8Br-cAMP. Importantly, GJ assembly between either S364ECx43/KO or S364ECx43/WT fibroblasts was stimulated by 8Br-cAMP, but that between S364ACx43/KO or S364PCx43/KO fibroblasts was not stimulated, indicating that phosphorylation or a negative charge at S364 is required for enhancement of GJ assembly by cAMP. Furthermore, GJ assembly between S364ACx43/WT fibroblasts could be stimulated by 8Br-cAMP, but could not be between S364PCx43/WT fibroblasts. Thus, S364PCx43 interferes with enhanced GJ assembly when coexpressed with WTCx43
The broad phenotypic spectrum of PPP2R1A-related neurodevelopmental disorders correlates with the degree of biochemical dysfunction
Purpose: Neurodevelopmental disorders (NDD) caused by protein
phosphatase 2A (PP2A) dysfunction have mainly been associated
with de novo variants in PPP2R5D and PPP2CA, and more rarely in
PPP2R1A. Here, we aimed to better understand the latter by
characterizing 30 individuals with de novo and often recurrent
variants in this PP2A scaffolding Aα subunit.
Methods: Most cases were identified through routine clinical
diagnostics. Variants were biochemically characterized for phosphatase activity and interaction with other PP2A subunits.
Results: We describe 30 individuals with 16 different variants in
PPP2R1A, 21 of whom had variants not previously reported. The severity
of developmental delay ranged from mild learning problems to severe
intellectual disability (ID) with or without epilepsy. Common features
were language delay, hypotonia, and hypermobile joints. Macrocephaly
was only seen in individuals without B55α subunit-binding deficit, and
these patients had less severe ID and no seizures. Biochemically more
disruptive variants with impaired B55α but increased striatin binding
were associated with profound ID, epilepsy, corpus callosum hypoplasia,
and sometimes microcephaly.
Conclusion: We significantly expand the phenotypic spectrum of
PPP2R1A-related NDD, revealing a broader clinical presentation of the
patients and that the functional consequences of the variants are more
diverse than previously reported
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PEG−peptide conjugates
The remarkable diversity of the self-assembly behavior
of PEG−peptides is reviewed, including self-assemblies formed by PEG−peptides with β-sheet and α-helical (coiled-coil) peptide sequences. The modes of self-assembly in solution and in the solid state are discussed. Additionally, applications in bionanotechnology and synthetic materials science are summarized
Behavioural and Developmental Interventions for Autism Spectrum Disorder: A Clinical Systematic Review
Background: Much controversy exists regarding the clinical efficacy of behavioural and developmental interventions for improving the core symptoms of autism spectrum disorders (ASD). We conducted a systematic review to summarize the evidence on the effectiveness of behavioural and developmental interventions for ASD. Methods and Findings: Comprehensive searches were conducted in 22 electronic databases through May 2007. Further information was obtained through hand searching journals, searching reference lists, databases of theses and dissertations, and contacting experts in the field. Experimental and observational analytic studies were included if they were written in English and reported the efficacy of any behavioural or developmental intervention for individuals with ASD. Two independent reviewers made the final study selection, extracted data, and reached consensus on study quality. Results were summarized descriptively and, where possible, meta-analyses of the study results were conducted. One-hundred-and-one studies at predominantly high risk of bias that reported inconsistent results across various interventions were included in the review. Meta-analyses of three controlled clinical trials showed that Lovaas treatment was superior to special education on measures of adaptive behaviour, communication and interaction, comprehensive language, daily living skills, expressive language, overall intellectual functioning and socialization. High-intensity Lovaas was superior to low-intensity Lovaas on measures of intellectual functioning in two retrospective cohort studies. Pooling the results of two randomized controlle
Informing the design of an authoring tool for developing social stories
Abstract. This paper describes the design of an authoring tool, ISISS (Improving Social Interaction through Social Stories), for supporting practitioners using social stories to enhance social interaction in children with Autism Spectrum Conditions (ASC). The goals of the research are: 1) to determine practitioners’ current procedures when working with social stories; 2) to discover how technology can better support such practitioners in the development and use of social stories that focus on improving children’s social communication skills. An exploratory study was conducted with experienced practitioners, resulting in a number of design principles. Two low-functioning prototypes were developed, and explored in a second study. Further work is discussed
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